Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects?

Research over the past 100 years (1) has repeatedly indicated caloric restriction protects against tumor development and increases longevity. However, more recent research, specifically two studies in monkeys (2), suggests these benefits may only be seen when caloric restriction is compared to an unhealthy diet or unhealthy controls (3).

The majority of older research on caloric restriction tested the effects of continuous energy restriction (CER) — that is, reducing the number of calories consumed every day for weeks, months, or years. Recent research has begun to focus on intermittent energy restriction (IER), which refers to any time-restricted form of calorie restriction, ranging from daily or extended fasts to alternate-day restricted feeding. This 2016 paper reviews research suggesting IER may reduce cancer risk, cancer progression, or cancer biomarkers.

At the time of this review’s publication, the majority of the research testing the impact of IER on cancer biomarkers or progression had been conducted in rat studies. The majority of these studies (4), but not all (5), indicated IER reduces rates of tumor development. IER more consistently prevented the growth and development of mammary tumors than prostate tumors, which may be explained in part by the interruptions in menstrual cycles induced by IER in rats (6).

Two other trials provide a potential explanation for these inconsistencies (7). In these studies, IER regimens involving complete or near-complete caloric restriction (>75%) on fasting days suppressed IGF-1 (insulin-like growth factor) levels and reduced tumor cell proliferation while less intensive fasts did not. It is worth noting, however, that rodents and humans respond differently to some fasting regimens, with rodents transitioning into ketosis more quickly and with less caloric restriction than fasting.

At the time of this paper’s publication, the authors did not find any research specifically testing the effects of IER on tumor development and/or progression in humans. They did note, however, that IER (often an alternate-day fast or similar program) rapidly reduces serum insulin levels and insulin receptor activity in humans, which is hypothesized to reduce cancer risk (8).

These conclusions are consistent with those featured previously on CrossFit.com. Valter Longo has argued the metabolic benefits of fasting are primarily due to fasting-induced suppression of IGF-1. Others similarly argue fasting triggers a “metabolic switch” that transitions the body from a state of high insulin, high glucose, and carbohydrate dependence to one of low insulin and glucose, reduced carbohydrate dependence, and increased fat burning; they also argue this metabolic transition reduces progression of metabolic disease and cancer risk factors.

The takeaway: Preliminary evidence, primarily in rodents, suggests fasting reduces cancer risk biomarkers (including IGF-1 and insulin levels) and may reduce the development and progression of certain tumors. More intensive fasts, such as complete fasting (100% caloric restriction) on alternating days, show more consistent benefits; more moderate fasts show equivocal clinical impact.

Notes

1. Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the Iowa women’s health study; Adult weight change and risk of postmenopausal breast cancer; Does bariatric surgery reduce cancer risk? A review of the literature; The influence of diet on transplanted and spontaneous mouse tumors; Recent advances in calorie restriction research on aging; “Control” laboratory rodents are metabolically morbid: Why it matters; Caloric restriction delays disease onset and mortality in rhesus monkeys; Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study
2. Caloric restriction delays disease onset and mortality in rhesus monkeys; Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study
3. Both studies compared monkeys fed ad libitum to monkeys fed a 25% calorie-restricted diet for their entire lives. One study found the calorie-restricted diet improved health across a variety of conditions, while one study did not observe benefits. The monkeys who benefitted from a calorie-restricted diet were compared to a less-healthy control group, which has been interpreted as evidence that continuous caloric restriction protects from the detrimental effects of an unhealthy diet but may not provide additional benefits beyond those seen with an otherwise healthy diet.
4. Apparent prolongation of the life span of rats by intermittent fasting; Alternate day feeding alters the circadian system, reduces breast cancer incidence and prolongs life; Suppression of mouse mammary tumor proviral DNA and protooncogene expression: Association with nutritional regulation of mammary tumor development; Weight-cycling decreases incidence and increases latency of mammary tumors to a greater extent than does chronic caloric restriction in mouse mammary tumor virus-transforming growth factor-alpha female mice; Prevention of mammary tumorigenesis by intermittent caloric restriction: Does caloric intake during refeeding modulate the response?; Serum insulin-like growth factor-I and mammary tumor development in ad libitum fed, chronic calorie-restricted and intermittent calorie-restricted MMTV-TGF-alpha mice; Effects of chronic vs. intermittent calorie restriction on mammary tumour incidence and serum adiponectin and leptin levels in MMTV-TGF-alpha mice at different ages; etc.
5. Failure to inhibit the formation of mammary carcinoma in mice by intermittent fasting; Effect of intermittent fasting with or without caloric restriction on prostate cancer growth and survival in SCID mice; Effect of intermittent fasting on prostate cancer tumor growth in a mouse model
6. Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice; Influence of underfeeding during the “critical period” or thereafter on carcinogen-induced mammary tumors in rats
7. Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding
8. The role for autophagy in cancer; IGF-IR inhibition: right direction, wrong pathway?; Banting memorial lecture 2012: Reversing the twin cycles of type 2 diabetes